NIH Exposed in Shock Mass Deception over COVID19 Treatment

Written by John O'Sullivan on April 23, 2020. Posted in Current News

At the very same time the National Institutes of Health (NIH), Dr Fauci and the media are deriding HCQ as ‘unsafe’ for treating COVID-19, the NIH backs dozens of clinical trials of Hydroxychloroquine (HCQ) as a safe treatment for cancer. How can that be?

On Tuesday an NIH panel reported that HCQ, the 75-year-old re-purposed malaria drug was unsafe  “because of the potential for toxicities.”

However, the NIH panel could only cite one piece of evidence –  a single study which was not even peer reviewed. 

For weeks the mainstream media has been dismissing the ‘Trump Cure’  because of “risky side effects“ since the US President and hundreds of doctors claimed it was highly effective. The MSM, Dr Fauci, WHO and the CDC are holding out for a vaccine instead.

Examination of the more detailed, prior peer-reviewed research cited below – where clear evidence shows no adverse affects from HCQ –  should have all alarm bells ringing.

HCQ is performing well in U.S. clinical trials as a potential treatment for many diseases, including cancer, such that we may be witnessing the dawn of a new era of cheap, effective cures for some of the most deadly maladies.

The contradictory claims coming from NIH raises grave questions about the reliability, motives and procedures employed by the NIH panel which dismissed HCQ as a treatment for COVID-19 patients on the basis of alleged “toxicities.”

The Guardian headline below typifies the media’s bias:

Doesn’t that smell like desperation to keep the mass lockdown in place?

NIH Incompetence or Dishonesty?

At minimum, this new revelation exposes a grave omission by the NIH. President Trump must surely initiate an urgent federal investigation.

Let’s now look at the emerging medical evidence:

The key document is Ecancermedicalscience. 2017; 11: 781. Published online 2017 Nov 23 [1]

We have select sections shown below:

Abstract

Chloroquine (CQ) and hydroxychloroquine (HCQ) are well-known 4-aminoquinoline antimalarial agents. Scientific evidence also supports the use of CQ and HCQ in the treatment of cancer. Overall, preclinical studies support CQ and HCQ use in anti-cancer therapy, especially in combination with conventional anti-cancer treatments since they are able to sensitise tumour cells to a variety of drugs, potentiating the therapeutic activity. Thus far, clinical results are mostly in favour of the repurposing of CQ.

However, over 30 clinical studies are still evaluating the activity of both CQ and HCQ in different cancer types and in combination with various standard treatments. Interestingly, CQ and HCQ exert effects both on cancer cells and on the tumour microenvironment. In addition to inhibition of the autophagic flux, which is the most studied anti-cancer effect of CQ and HCQ, these drugs affect the Toll-like receptor 9, p53 and CXCR4-CXCL12 pathway in cancer cells.

In the tumour stroma, CQ was shown to affect the tumour vasculature, cancer-associated fibroblasts and the immune system. The evidence reviewed in this paper indicates that both CQ and HCQ deserve further clinical investigations in several cancer types. Special attention about the drug (CQ versus HCQ), the dose and the schedule of administration should be taken in the design of new trials.

….

Chloroquine (CQ) and hydroxychloroquine (HCQ) are both 4-aminoquinoline agents that have been used for more than 70 and 50 years ….. Although HCQ and CQ differ only by one hydroxyl group, the addition of this hydroxyl group results in an important decrease in toxicity….. Both drugs are available as generic products and mentioned on the WHO list of essential medicines…..

Toxicity

Short-term administration of CQ or HCQ rarely causes severe side effects…

Pre-clinical evidence in cancer—in vivo

CQ and HCQ have been extensively studied both in vitro and in vivo in various cancer types…..

Both drugs can be administered as monotherapy or as adjuvant agents to increase the efficacy and to limit drug resistance of standard anti-cancer therapy….. Starting with in vivo studies that observed beneficial effects of CQ administration in cancer, Jutten et al noted a delayed tumour growth in mice bearing epidermal growth factor receptor (EGFR)-overexpressing glioblastoma xenografts in response to CQ administration. In addition, the time to reach four times the initial tumour volume was significantly longer in the CQ-treated group [16].

They observed that the number of mitotic cells was significantly reduced and the number of apoptotic cells was increased after CQ administration [17].

In addition, a significant reduction of tumour volume and tumour incidence was shown by Song et al [18] in mice bearing liver cancer stem cells and Hu et al [19] observed significant tumour growth and weight reduction in an orthotopic xenograft model of liver cancer after CQ administration. Lakhter et al [20] demonstrated that CQ significantly reduced both tumour volume and tumour mass in a human melanoma xenograft model. Zheng et al [21] showed reduced tumour progression and prolonged survival time (not significant) in colon cancer-bearing mice when administering either 25 or 50 mg/kg of CQ.

Doses of 25 and 50 mg/kg of CQ both significantly increased survival time and reduced primary tumour volume in mice implanted with a highly metastasizing breast cancer cell line, as shown by Jiang et al. Interestingly, the number and diameter of lung metastases was reduced as well, and CQ enhanced tumour cell apoptosis in the high dose group [22].

The incidence of mammary tumours and their growth rate was significantly lower and tumour onset was delayed in CQ-pre-treated rats after being subjected to mammary adenocarcinoma induction using N-methyl-N-nitrosourea (NMU), as shown by Loehberg et al. In wild-type BALB/c mice transplanted with mammary ducts of BALB/c p53-null mice, CQ pre-treatment did not affect tumour incidence [23]. Maclean et al confirmed that CQ could not prevent spontaneous tumour formation in p53-deficient mice. In contrast, intermittent CQ administration significantly reduced the tumour development and doubled the overall survival (OS) of Eμ-Myc mice [24].

Furthermore, Sun et al showed that CQ administration is effective in reducing tumour growth in rats with established hepatocarcinoma. In contrast, CQ promoted tumour development in the earlier so-called dysplastic stage, clearly illustrating the dual role of autophagy in tumour formation (see section on mechanisms of action) [25]. Finally, Maes et al [26] reported that either a dose of 50 mg/kg or a dose of 100 mg/kg of CQ can reduce tumour growth and cell proliferation, dependent on the cell type. Of note, this study showed that CQ not only inhibits autophagy but also affects the tumour microenvironment and tumour vasculature. The exact working mechanisms will be clarified in the section on mechanisms of action.

Some studies noted that the efficacy of CQ application in anti-cancer therapy depends on the tumour type that is being treated and suggested that the autophagy dependency of tumour cells might play a role [27, 28].

Combination therapy

Table 2 summarises the information from articles that studied the effect of CQ (n = 46) or HCQ (n = 5) in vivo in combination with other therapies….Interestingly, CQ and HCQ have already been tested in combination with over 40 other drugs in preclinical cancer research. Both CQ and HCQ can effectively increase the efficacy of various anti-cancer drugs, which is further explained in the section on mechanisms of action.

Human data

Numerous clinical trials in which either CQ or HCQ is being used to treat patients with a range of cancer types are registered in clinical trial databases. In clinical trials, these drugs are most often administered in combination with other anti-cancer agents….

CQ

Glioma and brain metastases

In May 1998, one of the first clinical trials on CQ use in cancer was started, which was an open, prospective, randomised controlled study with 18 glioblastoma multiforme (GBM) patients [38].

In the abstract of this study, the authors reported that adjuvant CQ administration significantly enhanced patient survival [33 ± 5 months for CQ-treated patients and 11 ± 2 months for controls (p < 0.0002)].

No important adverse effects were noted in this trial. [emphasis added]

After the observation of promising outcomes in five recurrent GBM patients treated with 250 mg CQ a day and reirradiation for 20 months [42], a phase-2 clinical trial tested the effects of CQ as a radio-sensitising agent in patients with brain metastases [43]. In this trial, 39 patients were administered whole-brain irradiation (30 Gy in 10 fractions over two weeks) in combination with a daily dose of 150 mg CQ for four weeks, while 34 patients received placebo instead of CQ in addition to the same radiation treatment. The overall response rate or OS did not improve after CQ administration.

However, the progression-free survival of brain metastases rate was increased (CQ-treated group: 83.9{154653b9ea5f83bbbf00f55de12e21cba2da5b4b158a426ee0e27ae0c1b44117} [95{154653b9ea5f83bbbf00f55de12e21cba2da5b4b158a426ee0e27ae0c1b44117} CI 69.4–98.4] and control group: 55.1{154653b9ea5f83bbbf00f55de12e21cba2da5b4b158a426ee0e27ae0c1b44117} [95{154653b9ea5f83bbbf00f55de12e21cba2da5b4b158a426ee0e27ae0c1b44117} CI 33.6–77.6] (at one year), relative risk: 0.31 [95{154653b9ea5f83bbbf00f55de12e21cba2da5b4b158a426ee0e27ae0c1b44117} CI 0.1–0.9, p = 0.046]). The absence of adverse effects and the improved local control of brain metastases indicate that CQ might be a useful addition to whole brain irradiation in patients with brain metastases…..

In a prospective, single-cohort study of 20 patients with brain metastases from solid tumours, 250 mg CQ daily was administered for five weeks in combination with whole-brain irradiation [44]. ….no adverse reactions were detected. [emphasis added]

HCQ

Solid cancers

The effect of HCQ and temsirolimus combination therapy was tested in 27 patients with advanced solid cancer during a phase-1 dose-escalating study and subsequently in 13 patients with metastatic melanoma at the phase-2 recommended dose [51]…..This study recommends an adjuvant HCQ dose of 600 mg, twice daily…..

…Next, the combinatory effect of HCQ and temozolomide was investigated in 40 cancer patients with advanced solid tumours and melanoma, and the recommended dose of 600 mg twice daily was confirmed [52]. HCQ was shown to successfully inhibit autophagy,…

The safety and preliminary efficacy of HCQ and vorinostat combination treatment was tested during a phase-1 study in 27 patients with advanced solid tumours [53].

Glioblastoma

The efficacy and safety of HCQ was studied in combination with radiotherapy and temozolomide in 92 GBM patients during a phase-1–2 study [55]. This study indicated a maximum tolerated dose (MTD) of 600 mg HCQ a day in this therapeutic setting…..

Lung cancer

The combination of HCQ with erlotinib can be used safely in daily doses of 150 mg erlotinib and 1000 mg HCQ, as determined by a phase-1 study in 27 patients with advanced non-small cell lung cancer (NSCLC) [57]……

Multiple myeloma

During a phase-1 study, the safety of the combination of HCQ and bortezomib was explored in 25 patients with relapsed or refractory myeloma [59]. A dose of 600 mg HCQ twice daily was reported to be safe and tolerable in combination with standard doses of bortezomib…..

Pancreatic cancer

The safety of the combination of pre-operative HCQ (1200 mg daily) and gemcitabine administration was demonstrated in 35 patients with pancreatic adenocarcinoma in a phase-1–2 trial [60]. This study reported promising clinical response markers (e.g. CA 19–9 biomarker and R0 resection rate). An exploratory analysis showed significantly improved disease-free survival and OS (15.03 versus 6.9 months and 34.83 versus 10.83 months, respectively) in patients for whom autophagy was sufficiently inhibited (n = 8) (at least 51{154653b9ea5f83bbbf00f55de12e21cba2da5b4b158a426ee0e27ae0c1b44117} increase in the autophagy marker LC3B-II in peripheral blood mononuclear cells) compared with other patients (n = 9)……

Next, a phase-2 study investigated the safety and efficacy of HCQ monotherapy with either 400 or 600 mg two times a day in 20 patients with previously treated metastatic pancreatic cancer, but no significant differences were observed between groups [61]….

Mechanism of action

Multiple hypotheses have been proposed on how CQ and HCQ exert their anti-cancer activity. Most studies reported the direct action of these drugs on cancer cells, but more recent studies have also mentioned important effects of CQ and HCQ on the tumour microenvironment. Based on preclinical studies, it is safe to say that CQ and HCQ have multiple mechanisms of action that might complement each other…..

Direct anti-tumour effects

The main and most studied anti-cancer effect of CQ and HCQ is the inhibition of autophagy, but other preclinically proven anti-cancer activities of the antimalarial agents include influencing the TLR9/nuclear factor kappa B (NF-κB) signalling pathway, the CXCL12/CXCR4 signalling pathway and the p53 pathway….

CQ and HCQ can activate caspase-3 and modulate the Bcl-2/Bax ratio inducing apoptosis in CLL, B-cell CLL and glioblastoma cells [17, 89, 98–100]. CQ-mediated cell-cycle-arrest and apoptosis was observed in breast cancer cells and was associated with a decrease in protein levels/activity of polo-like kinase 1 (Plk-1), ERK1/2 Akt and cell division cycle 25C (CDC25C). The same study described induction of caspase-3-mediated spindle abnormalities and down regulation of the mitochondrial transmembrane potential by CQ [101]. A decreased lung cancer cell growth after low CQ concentrations was ascribed to an increased lysosomal volume and a phosphatidylcholine-specific phospholipase C involvement (PC-PLC). Higher CQ concentrations still induce apoptosis and necrosis, but likely via different processes [102]…..

CQ can inhibit hypoxia-stimulated metastasis via modulation of hypoxia-inducible factor 1α (HIF-1α), vascular endothelial growth factor (VEGF), and epithelial mesenchymal transition (EMT) as shown in a cholangiocarcinoma cell line [105].

In triple-negative breast cancer, CQ was shown to eliminate cancer stem cells through reduction of the expression of Janus-activated kinase 2 and DNA methyl transferase 1 [106] or through induction of mitochondrial dysfunction, subsequently causing oxidative DNA damage and impaired repair of double-stranded DNA breaks [107].

Of note, various studies showed growth inhibition of melanoma cells after CQ administration, but this inhibition was more pronounced in pigmented melanoma, which could be ascribed to CQ’s high affinity for melanin [108]. There is also some contradictory evidence about a potential link between Burkitt’s lymphoma incidence and CQ administration [109, 110]….

Modulation of tumour micro-environment

Immunomodulation

An increasing level of research is addressing the essential role of the immune system in cancer development. Activating the immune system against cancer cells is becoming a promising therapeutic approach [111], as immune cells have the ability to detect and destroy malignant cells [66].

Interestingly, autophagy and lysosomal function have been found to be involved in both innate and adaptive immunity [66]. Therefore, inhibitors of these processes such as CQ and HCQ could potentially modulate the immune system and subsequently influence tumour development….

A recent study showed that CQ normalises tumour vessels, independent of its autophagy inhibitory effect, through reduction of vessel density and improvement of cell alignment and formation of tight junctions. At the molecular level, CQ alters endosomal Notch1 trafficking and signalling in endothelial cells, hereby increasing the quiescent phenotype of the endothelial cells [26, 116]. Of note, systemic CQ administration has also been shown to reduce the vascular toxicity of the intratumorally administered, anti-tumour agent Transferrin-CRM107 in in vivo glioma models [117]…..

CQ can prevent the entrapment of protonated chemotherapeutic drugs by buffering the extracellular tumour environment and intracellular acidic spaces [112]. For example, CQ can reduce the endosomal sequestration of certain drugs by raising the endosomal pH and, thus, increase their efficacy (e.g. doxorubicin, daunorubicin and mitoxantrone) [122–124]. Vezmar et al [125, 126] suggested that CQ influences multidrug resistance protein-mediated doxorubicin resistance by binding the multidrug resistance protein….

Our take

The final goal of this literature review was to inform further research and trials on repurposing CQ and HCQ as anti-cancer agents, as done previously for other agents [138]. In addition, the ideal dose, route of administration, and therapeutic schedule that should be applied in anti-cancer therapy was explored. Finally, the potential difference in efficacy and toxicity between CQ and HCQ has been investigated.

Efficacy of CQ and HCQ in anti-cancer therapy

The vast majority of preclinical studies on the effect of CQ monotherapy in cancer have reported a positive therapeutic effect, but the study parameters, doses, animal models and tumour types differ strongly between studies, complicating the interpretation of the results. Preclinical studies investigating the effect of HCQ in cancer are limited. Therefore, follow-up in vivo studies are warranted. A risk of publication bias exists so we cannot guarantee that all negative results have been reported.

Combination therapy with CQ or HCQ and existing anti-cancer therapies has been extensively studied in preclinical research, both in vitro and in vivo. The majority of these studies have reported an improved therapeutic efficacy as compared with monotherapy with existing anti-cancer drugs. Most studies hypothesise that CQ and HCQ could increase the efficacy of other anti-cancer drugs by blocking pro-survival autophagy. Because not all studies measured autophagy levels in vivo, it is difficult to determine to what extent the other proposed mechanisms play a role. Table 2 is limited to studies that tested CQ or HCQ in combination with conventional anti-cancer agents in vivo, but there are many other combinations that have only been tested in vitro.

Finally, multiple clinical trials have investigated, or are going to investigate, the use of CQ and HCQ in different cancer types, always in combination with other anti-cancer drugs. The availability of clinical results is limited now, as most trials are still recruiting or ongoing, and those that have been completed focused primarily on safety and tolerability of CQ and HCQ in cancer.

In short, these drugs have been found safe and tolerable in all completed studies and the anti-cancer effect of both compounds is promising.  [emphasis added]

[1] see: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5718030Verbaanderd C, Maes H, Schaaf MB, et al. Repurposing Drugs in Oncology (ReDO)-chloroquine and hydroxychloroquine as anti-cancer agents. Ecancermedicalscience. 2017;11:781. Published 2017 Nov 23. doi:10.3332/ecancer.2017.781

About the author: John O’Sullivan John is CEO and co-founder (with Dr Tim Ball) of Principia Scientific International (PSI).  John is a seasoned science writer and legal analyst who assisted Dr Ball in defeating world leading climate expert, Michael ‘hockey stick’ Mann in the ‘science trial of the century‘. O’Sullivan is credited as the visionary who formed the original ‘Slayers’ group of scientists in 2010 who then collaborated in creating the world’s first full-volume debunk of the greenhouse gas theory plus their new follow-up book.

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